In the development of oral formulations many factors must be considered. They include: (1) the drug should be stable in the presence of formulation excipients; (2) the drug should be recovered from the formulation excipients; (3) the drug should exhibit acceptable dissolution characteristics from the formulation; (4) processing should allow for acceptable content uniformity; and (5) the formulation should have acceptable physical characteristics. Many of these aspects are addressed in preformulation through drug-excipient compatibility studies. Chemical stability is often the primary concern with drug-excipient compatibility evaluations.
The drug-excipient physical interactions, however, can also affect the formulation performance and the development of analytical methodology. For instance, although the interactions resulting in the adsorption of drugs onto solid dosage form excipients are generally of a weak type such as Van der Waals forces and hydrogen bonding, they have been shown to influence and affect content uniformity of solid dosage forms.
For example, in the manufacture of tablets, segregation of medicament adsorbates of a small particle size from solid dosage form excipients can occur due to the electrostatic nature of the adsorbates. Once the adsorbates segregate, they re-agglomerate into tiny spheres which are high in drug concentration. This is visually evident and can be observed in the blend uniformity and solid dosage form uniformity. The segregation of medicament adsorbates of a small particle size, therefore, contributes to variation in the drug content of solid dosage forms such as tablets which is unfavorable due to the unreliable delivery of a medicament.
An example of a medicament adsorbate which has demonstrated the unfavorable drug-excipient physical interactions are those which are prepared from magnesium trisilicates. The adsorption of a medicament onto magnesium trisilicates in the preparation of a medicament adsorbate has been taught in the literature as a method to render bitter drug principles tasteless in liquid, tablet and chewable dosage forms which become readily bioavailable when the adsorbate reaches the low pH acid media of the stomach. Unfortunately, the resulting adsorbate formed has a very smart particle size (30 microns) and is very electrostatic. As indicated above, these electrostatic forces cause the adsorbate to segregate from the excipients and re-agglomerate into tiny spheres which are high in drug concentration. Solid dosage forms prepared with the medicament adsorbates vary by ten percent or more in their drug concentration due to the lack of blend uniformity.
It can be understood that it would be an improvement to the art if one could reduce the electrostatic properties of the adsorbate without effecting taste masking. Reduction of the electrostatic forces would improve the processing of adsorbates such as those containing magnesium trisilicate and provide for a more uniform composition.
U.S. Pat. No. 3,085,942 to Magid discloses the formation of an antitussive composition using dextromethorphan hydrobromide and its acid addition salts adsorbed, in part, on magnesium trisilicate. Magid notes that particle size of the magnesium trisilicate is not critical in preparing the adsorbates and that average particle sizes of about 0.1 to about 150 microns are usable. Magid also notes that when the ingredients are intimately mixed, the bitter taste associated with dextromethorphan is reduced or eliminated. The adsorbate may be mixed with other ingredients to form compressed tablets, candy lozenges, chewing gum tablets and the like.
U.S. Pat. No. 4.581,232 to Peters et al. discloses a medicament adsorbate containing a magnesium trisilicate having a surface area of at least 400 m.sup.2 /g and having a flake-like structure with multiple interstitial spaces, and having adsorbed therein from about 1% to about 20% by weight of the adsorbate of a medicament drug, wherein the medicament drug is an antitussive such as dextromethorphan hydrobromide. This patent further discloses that the adsorbate may be formulated with pharmaceutically acceptable carriers, i.e. diluents, binders and adhesives, lubricants, disintegrants, colorants, flavorings, sweeteners, to prepare medicated compositions which offer a variety of textures to suit particular applications. Such compositions may be in the form of a lozenge, tablet, toffee, nougat, chewy candy, chewing gum, and so forth.
U.S. Pat. No. 4,647,459 to Peters et al. discloses a confectionery composition containing a magnesium trisilicate having a surface area of at least 400 m.sup.2 /g and having a flake-like structure with multiple interstitial spaces, and having adsorbed therein from about 1% to about 20% by weight of the adsorbate of a medicament drug. Such compositions may be in the form of a lozenge, tablet, toffee, nougat, chewy candy, and so forth.
The U.S. patents discussed herein are expressly incorporated by reference.